Drug interference with the Jaffe' method for the determination of creatinine (picric acid) by the drugs cefoxitin and phenacemide were studied. A. Cefoxitin: The quantitative degree of interference caused by cefoxitin varies with the analytical system. It is less when run on the SMAC (Technicon Inc.) than when run on other instruments because the dialysis step reduces the molar ratio of cefoxitin to creatinine by half. A study varying the NaOH concentration and comparing rate constants showed that both creatinine and cefoxitin react with picrate in an identical storchiometric manner. All members of the cephalosporin and cephamycin antibiotics tested (c 10) react with picrate though to a lesser degree and not as fast as cefoxitin, the acetomido-groups on the molecules being the likely sites of reaction. Further delineation of the reactive sites is proceeding. Cefoxitin reacts with picrate by both the fast and slow reaction, both of which buttress the reaction of creatinine with picrate. B. The interference caused by phenacemide varies according to instrument and is positive with the ASTRA-8 (Beckman) and negative with the aca (Du Pont). It is negative on the aca, because the product loses absorbance after 30 seconds. The significance of the project lies in the eventual ability to identify drugs which interfere and elimination of the interference by knowledge of the mechanistic principles of the picrate reaction.